?-lactam antibiotics are the most widely used antibiotic class in the U.S., accounting for more than 50% of antibacterial prescriptions. Among other roles, they are critical therapeutics for difficult-to-treat infections due to gram negative pathogens such as Salmonella spp., Shigella spp., E. coli, Klebsiella pneumoniae, and Enterobacter spp. However, the utility of this class of antibiotics is being rapidly compromised by the alarming spread of new ?-lactamase resistance mechanisms; enzymes produced by bacteria that hydrolytically inactivate ?-lactam antibiotics. A particularly important concern is te lack of orally bioavailable ?-lactam/??-lactamase inhibitor (BLI) combinations capable of addressing this emerging challenge, both in the Biodefense arena and in the hospital/community settings. Orally available ?-lactam combinations with legacy BLIs (e.g., amoxicillin/clavulanic acid or Augmentin(R)) demonstrate some activity against Gram negative pathogens expressing Ambler Class A Extended Spectrum Beta Lactamases (ESBLs), but lack activity against organisms expressing Class A carbapenemases (KPC-type), Class C cephalosporinases (chromosomal and plasmidic), and Class D oxacillinases, including carbapenemases. We have identified a novel ?-lactamase inhibitor series with potent and broad spectrum activity against this new wave of serine ?-lactamases and high selectivity for bacteria. These compounds rescue the activity of the orally bioavailable cephalosporin Ceftibuten in MDR-strains of Gram negative Enterobacteriaceae, including Category B and C priority pathogens Salmonella spp., and MDR- E. coli and K. pneumoniae. Moreover, we have shown that designed prodrug prototypes in the series can demonstrate striking oral bioavailability in rodents, and rescue Ceftibuten activity in murine models of bacterial infection. The objectives of this project are to execute a comprehensive oral prodrug approach on the most broad- spectrum parent BLIs in the series, select the first Development Candidate (DC), and advance the selected DC to IND filing for clinical development in combination with Ceftibuten.